Cell-autonomous immune gene expression is repressed in pulmonary neuroendocrine cells and small cell lung cancer
Ling Cai, Hongyu Liu, Fang Huang, Junya Fujimoto, Luc Girard, Jun Chen, Li Y, Yu‐An Zhang, Dhruba Deb, Victor Stastny, Karine Pozo, Christin S. Kuo, Gaoxiang Jia, Chendong Yang, Wei Zou, Adeeb Alomar, Kenneth E. Huffman, Mahboubeh Papari-Zareei, Lin Yang, Benjamin J. Drapkin, Esra A. Akbay, David S. Shames, Ignacio I. Wistuba, Tao Wang, Jane E. Johnson, Guanghua Xiao, Ralph J. DeBerardinis, John D. Minna, Yang Xie, Adi F. Gazdar
Abstract
Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed "variant" due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings may help guide the design of treatment regimens in SCLC.